Central tolerance

B cell central tolerance

Central tolerance is a critical process in the immune system that helps prevent the body from attacking itself, leading to autoimmunity. This mechanism operates primarily in the thymus for T cells and in the bone marrow for B cells, which are essential components of the adaptive immune system. Central tolerance is responsible for eliminating self-reactive lymphocytes during their development, ensuring that these cells do not initiate an immune response against the body's own tissues.

Mechanism

The process of central tolerance involves several key steps. In the thymus, immature T cells, known as thymocytes, undergo positive and negative selection. Positive selection ensures that T cells capable of recognizing self-major histocompatibility complex (MHC) molecules survive, while negative selection eliminates those T cells that have high affinity for self-antigens presented by MHC molecules. Similarly, in the bone marrow, developing B cells that react strongly to self-antigens are either edited to change their specificity or induced to undergo apoptosis, a process of programmed cell death.

T Cell Central Tolerance

During T cell development in the thymus, thymocytes expressing T cell receptors (TCRs) that fail to recognize self-MHC molecules are subjected to death by neglect, as they will not receive the necessary survival signals. Conversely, thymocytes that recognize self-MHC molecules with moderate affinity receive signals for survival and maturation, a process known as positive selection. Negative selection targets thymocytes that bind too strongly to self-antigens presented by MHC molecules, leading to their apoptosis. This process is facilitated by thymic epithelial cells and dendritic cells, which present self-antigens to developing T cells.

B Cell Central Tolerance

In the bone marrow, immature B cells that bind self-antigens with high affinity undergo receptor editing, an attempt to change their antigen specificity. If receptor editing fails to eliminate self-reactivity, the self-reactive B cells are eliminated through apoptosis. This ensures that emerging B cells are tolerant to self and reduces the risk of autoimmunity.

Importance

Central tolerance is crucial for preventing autoimmunity, a condition where the immune system mistakenly attacks the body's own cells and tissues. By eliminating self-reactive lymphocytes during their development, central tolerance helps maintain self-tolerance and immune homeostasis. However, central tolerance is not foolproof, and some self-reactive cells may escape into the peripheral circulation. Peripheral tolerance mechanisms exist to deal with these cells, including anergy, suppression by regulatory T cells, and deletion.

Clinical Significance

Defects in central tolerance can lead to the development of autoimmune diseases, such as Type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus. Understanding the mechanisms of central tolerance is crucial for developing therapies aimed at restoring self-tolerance in autoimmune conditions. Additionally, manipulating central tolerance pathways has potential implications in transplantation and cancer immunotherapy, where enhancing or inhibiting immune responses can be beneficial.

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